Mycobacterium tuberculosis (Mtb) is known to subvert immune responses to establish infection and cause disease. Thus, host-directed therapy (HDT), as adjunctive treatment to traditional antitubercular regimens, is an attractive strategy. In this proposal, we will investigate the novel hypothesis that statins (HMG-CoA reductase inhibitors) can serve as adjunctive HDT, permitting treatment shortening for drug-susceptible TB and improving lung inflammation and function. Among the most commonly prescribed drugs, statins have lipid-lowering and immunomodulatory properties. Accumulation of lipids in macrophages harboring Mtb has been associated with persistence and phenotypic tolerance to front-line drugs, which leads, in turn, to prolonged treatment duration. We and others have shown that statins, while lacking a direct antimicrobial effect, reduce Mtb growth and infection-induced lipid accumulation in macrophages, and promote phagosomal maturation and autophagy. We also have demonstrated that adjunctive therapy with simvastatin enhances the bactericidal activity of the first-line anti-TB regimen in a standard mouse model of chronic TB infection and reduces the time required for cure. Furthermore, statins have been shown to reduce TB-induced lung pathology in the mouse model. In this application, we propose preclinical studies in macrophages and in a clinically relevant murine model that will allow us to compare activity and exposure-response relationships of various statins and to identify the most promising compound and doses to test clinically. Upon selection of the lead statin, we will conduct a two-stage, proof-of-concept clinical trial, in which patients with drug-susceptible, pulmonary TB (with or without HIV co-infection) will be recruited through existing NIH- and South African MRC-supported clinical sites in Soweto and Matlosana, South Africa. Participants in Stage 1 will be randomized to receive the first-line antitubercular regimen with or without the lead statin provided at two different doses for evaluation of safety, PK, and drug interactions, and for selecting the statin dose for Stage 2. In Stage 2, we will determine the ability of the statin, when given in combination with first-line TB treatment, to shorten the time required for sputum culture conversion to negative, as well as other secondary clinical, radiological, microbiological, and laboratory-based outcomes. The plasma concentrations of statin measured in the clinical trial, as well as published data, will be used to guide statin exposures to elucidae the statin's effects on known anti-TB mechanisms of macrophages, including infection-induced lipid accumulation, phagosome maturation and autophagy, and secretion of pro-inflammatory cytokines. This knowledge will help design future Phase III studies. Our proposal leverages an ongoing collaboration between multidisciplinary teams of investigators at Johns Hopkins University School of Medicine, University of the Witwatersrand DST/NRF Centre of Excellence, and Rutgers New Jersey Medical School. Our findings have the potential to substantially advance our understanding of host-organism interactions and clinically validate statins as an adjunctive HDT that can shorten the duration of TB treatment and improve lung function-related outcomes.